Substituted propenone compounds have been investigated to a limited degree for their estrogenic properties and their potential as anti-carcinogenic, anti-fungal, anti-proliferative and anti-oxidant therapeutics.
These investigations have been adjunct to studies involving flavanoid and isoflavanoid compounds since substituted propanones and propenones are open ring structures possibly being precursors to or metabolites of flavones and isoflavones.
Flavanoid and isoflavanoid compounds are attracting increased attention as several are known to display significant estrogenic activity, as well as anti-carcinogenic, antifungal, antiproliferative properties and anti-oxidative effects.
It has been postulated that the estrogenic activity of isoflavanoid compounds results from the distinct similarities in structure, molecular weight and polarities to estrogens which enable them to bind to mammalian estrogen receptors.
Additionally, the benzopyran moiety of several isoflavonoids is structurally similar to the fused rings of estradiol, and hydroxyl groups are critically located enabling binding to estrogen receptor proteins. Accordingly, the plant-derived isoflavonoids are increasingly referred to as phytoestrogens.
Daidzein and genistein are naturally occurring isoflavanoid compounds which are known to readily bind to estrogen receptors. These compounds are poly hydroxy-substituted isoflavones which show estrogenic activity and anti-proliferative activity against a number of cancer cell lines. Their partially methylated pre-cursors, formononetin and biochanin A, are also naturally occurring isoflavones found in high concentrations in red clover. Both of these molecules, however, are considerably less effective than their hydroxyl homologues eg. daidzein and genistein, in binding to estrogen receptors and as anti-proliferative agents.
Recent investigation as reported in WO 00/66575 has shown that isoflavanoid compounds which demonstrate vicinal diol substitution show increased therapeutic activity over daidzein and genistein. The vicinal diol substitution may be afforded by 6,7-dihydroxy substitution in the benzopyran moiety of the isoflavonoid compounds or by 3′,4′-dihydroxy substitution on the 3-phenyl substituent.
Investigations by Hong et al (2002) demonstrated significant anti-proliferative properties of 2-dehydro-0-demethyl angolensin, an apolyhydroxyisoflavone metabolite, against a number of human cancer cell lines. This study suggested that the growth inhibitory properties of certain isoflavones may be effected by metabolite products rather than the parent isoflavone itself.
This invention commenced as a study of flavonoid and isoflavonoid metabolites to confirm the results of earlier workers with the synthesis of poly hydroxyl phenyl propanones and propenones.
Counter intuitively, the inventor of this invention has discovered that fully or partially methoxylated and otherwise substituted aryl propen-1-ones afford enhanced estrogenic and antiproliferative activity relative to closed ring isoflavones and also relative to poly hydroxy propanones and propen-1-ones.
Furthermore, the synthetic pathways for obtaining the methoxy derivatives are simpler than their hydroxy analogues as there is no requirement for protecting groups, and their subsequent removal. The reduction in the number of synthetic steps also minimises potential contaminants, leading to more straightforward purification processes. The resultant compounds are readily characterised.